Obesity, insulin resistance and diabetes are a growing public health issue that has reached epidemic proportions in Western society. There is a constant need to devise new therapies, including behavioral and pharmacologic interventions that offer long-term efficacy. We have recently, and unexpectedly, found that chronic adaptation to continuous hypoxia (CH; i.e. simulating altitude exposure) can increase insulin sensitivity in lean mice. Moreover, even exposure to mild nocturnal hypoxia improves insulin sensitivity in obese mice. The literature and our own data suggest that increased circulating nitrite, the predominant source of bioactive nitric oxide (NO) during hypoxia, likely contributes to the metabolic benefits of CH. Our data show that combining hypoxia and nitrite administration is a potent stimulus for upregulating hypoxia inducible factor-1 (HIF-1), increasing mitochondrial biogenesis, and decreasing oxidative phosphorylation overload in muscle. We will examine the relative roles of increased blood flow to muscle versus direct metabolic adaptations at the level of the myoctye. Furthermore, we will examine the contribution of the constitutive NO-soluble guanylate cyclase (sGC) pathway versus non-sGC pathways in mediating increases in insulin sensitivity and muscle glucose uptake in response to hypoxic exposure and nitrite administration. Our overarching hypothesis is that chronic exposure to mild nocturnal CH and exogenous nitrite administration increases muscle glucose uptake through activation of HIF-1 and increased bioavailability of NO. The following four Specific Aims will be tested in mice with genetic and diet-induced obesity. Aim 1: To determine the effects of chronic hypoxia on insulin sensitivity in obese mice. Aim 2: To (a) determine the effects of chronic nitrite administration on insulin sensitivity under normoxic and hypoxic conditions in obese mice and (b) to assess the role of increased blood flow versus muscle-specific effects on increasing insulin sensitivity and muscle glucose uptake. Aim 3: To determine the role of HIF-1 in mediating increases in muscle glucose/insulin delivery and muscle glucose uptake with chronic hypoxic exposure and nitrite administration. Aim 4: To determine the mechanisms by which bioavailable NO increases muscle glucose uptake through NO-sGC pathways with chronic hypoxic exposure and nitrite administration. Our studies will not only provide new mechanistic insights into metabolic dysfunction associated with obesity and insulin resistance, but also examine the potential of two, as yet untested, interacting novel therapies for improving insulin sensitivity.